Hepatitis C virus (HCV) infection presents a significant worldwide health problem that affects approximately 170 million people, with about 30,000 new cases in the United States each year. HCV is not easily cleared by the host's immunological defenses, and as many as 85% of the people infected with HCV become chronically infected, often resulting in chronic liver disease, including cirrhosis and hepatocellular carcinoma (Hoofnagle, J. H. 1997, Hepatology 26: 15S–20S). Chronic hepatitis C is the leading cause of chronic liver disease, the leading indication for liver transplantation in the United States, and The Centers for Disease Control and Prevention estimates that chronic hepatitis C virus infection is responsible for approximately 10,000 to 12,000 deaths in the United States annually. This number is expected to triple in the next 10 to 20 years without effective intervention.
HCV belongs to the family Flaviviridae, genus hepacivirus, which includes three genera of small, enveloped positive-strand RNA viruses. The 9.6 kb genome of HCV consists of a long open reading frame (ORF) flanked by 5′ and 3′ non-translated regions (NTR's). The polyprotein is cleaved both co- and post-translationally by cellular and viral proteases into at least four structural and six nonstructural (NS) proteins. One of these nonstructural proteins is NS5B, the RNA-dependent RNA polymerase, which plays a central role in viral RNA replication of HCV as well as other viruses of the Flaviviridae family.
Unfortunately, the development of effective vaccines for prophylaxis and/or treatment of HCV has been impeded by various virus-specific difficulties, and especially immune evasion. Thus, current treatment of HCV predominantly employs therapeutics that reduce serum HCV levels via monotherapy with (pegylated) interferon-alpha or in combination therapy with the nucleoside analogue ribavirin. While monotherapy results in only 10% sustained virological response (SVS), combination therapy has been shown to improve sustained responses to 54–56% (Michielsen P. et al., 2002, Acta Gastroenterol Belg 65(2), 90–94). Clearly, effective antiviral therapies that prevent and alleviate complications suffered by millions of individuals chronically infected with HCV are needed.
Quinoxalines are a well-known class of compounds (O. Hinsberg, J. Liebigs Ann. Chem . 237, 327 (1986)), and selected quinoxaline derivatives have been described for use in various therapeutic applications. For example, selected 4-N-aroyl-, arylacyl- and arylsulfonyl-3,4-dihydroquinoxalin-2(1H)-ones were described as anti-inflammatory agents in a series of patent applications by Sumitomo Chem. Co. Ltd. (see e.g., JP 17,137/69, JP 17,136/69, JP 7,008/422, BE 706,623), and 3,4-Dihydroquinoxalin-2(1H)-one-3-carboxamides were described as anti-inflammatory compounds in U.S. Pat. No. 3,654,275. In another example, selected pyridinyl-alkyltetrahydropyrazino[1,2-a]quinoxalinone derivatives were described in U.S. Pat. Nos. 4,203,987 and 4,032,639 as antihypertensive and antisecretory reagents. Furthermore, 4-N-benzenesulfonyl-3,4-dihydroquinoxalin-2(1H)-one-1-alkyl carboxylic acids were reported as aldose reductase inhibitors as described in European Patent Application EP 266,102, and selected quinoxalines were described in U.S. Pat. No. 6,369,057 as therapeutic agents against HIV. However, none of the known quinoxaline derivatives have been demonstrated to exhibit activity against RNA-dependent RNA polymerases, and especially the RNA polymerase NS5B of HCV. The absence of RNA-dependent RNA polymerases in mammals, and the fact that this enzyme appears to be essential to viral replication, would suggest that the NS5B polymerase is an ideal target for anti-HCV therapeutics.
Thus, while numerous therapeutic compounds for treatment of HCV infections are known in the art, all or almost all of them suffer from various disadvantages. Therefore, there is still a need to provide compositions and methods for effective treatment of viral infections, and especially for the effective treatment of HCV infections.